ABSTRACT Aging is the single largest risk factor for many common diseases that burden public health. The major goal of this application is to understand the pathogenesis of age-related diseases resulting from deleterious alterations of the dermal extracellular matrix (ECM) microenvironment. This application employs novel mouse models of accelerated skin connective tissue aging and therefore addresses a need identified by the NIH for development and characterization of animal models for aging research (FOA PA-13-155). The dermis comprises the bulk of skin and confers strength and resiliency. The dermis is primarily composed of collagenous ECM. This ECM is produced, organized and maintained by fibroblasts. Our recent studies reveal that dermal fibroblasts, in aged human skin in vivo, express elevated levels of a protein called CCN1. We find that elevated CCN1 causes fibroblasts to express altered levels of numerous secreted proteins that deleteriously impact skin function. CCN1-induced alterations include: 1) reduced collagen production, which causes dermal thinning; 2) elevated levels of collagen-degrading enzymes, which cause ECM fragmentation; and 3) increased levels of proinflammatory cytokines, which promote aging associated inflammation (inflammaging). Importantly, these CCN1-induced alterations are major features of aged human skin. We refer collectively to these alterations as ?Age-Associated Dermal Microenvironment (AADM)?. Based on these data, we have created a transgenic mouse model (CCN1col-tg) with increased expression of CCN1 by fibroblasts. These mice display accelerated aging and AADM. In addition, these mice exhibit significantly increased susceptibility to formation of skin tumors. Based on our findings, we hypothesize that age-related elevation of CCN1 by dermal fibroblasts causes AADM, which promotes skin aging and age-related skin diseases. Specific Aim 1 will test the hypothesis that healthy young dermal microenvironment functions as tumor suppressor, while AADM act as a tumor promoter. Specific Aim 2 will determine molecular mechanisms by which CCN1 promotes AADM. Specific Aim 3 will utilize mechanism-based intervention to inhibit CCN1-induced AADM and skin cancer formation. This proposal is innovative and highly impactful because it: 1) utilizes novel mouse models to investigate new concepts of aging, i.e. AADM and its role in aging and age-related diseases, and 2) brings into focus the importance of the interplay between the extracellular microenvironment and decline of cell function during the aging process.